Synthesis and composition of rapafucin libraries

ABSTRACT

A Rapafucin library containing compounds of the general structure, (A) and (E), and a synthesis of these compounds are provided.

RELATED APPLICATIONS

This application is a 35 USC § 371 National Stage application of International Application No. PCT/US2017/016481 filed Feb. 3, 2017, now pending; which claims the benefit under 35 USC § 119(e) to U.S. application Ser. No. 62/291,437 filed Feb. 4, 2016, now expired. The disclosure of each of the prior applications is considered part of and is incorporated by reference in the disclosure of this application.

GRANT INFORMATION

This invention was made with government support under National Institutes of Health grant DP1CA174428. The government has certain rights in the invention.

BACKGROUND OF THE INVENTION Field of the Invention

The invention relates generally to hybrid cyclic molecules, and more specifically to hybrid cyclic libraries based on the immunophilin ligand family of natural products FK506 and rapamycycin.

Background Information

The macrocyclic natural products FK506 and rapamycin are approved immunosuppressive drugs with important biological activities. Both have been shown to inhibit T cell activation, albeit with distinct mechanisms. In addition, rapamycin has been shown to have strong anti-proliferative activity. FK506 and rapamycin share an extraordinary mode of action; they act by recruiting an abundant and ubiquitously expressed cellular protein, the prolyl cis-trans isomerase FKBP, and the binary complexes subsequently bind to and allosterically inhibit their target proteins calcineurin and mTOR, respectively. Structurally, FK506 and rapamycin share a similar FKBP-binding domain but differ in their effector domains. In FK506 and rapamycin, nature has taught us that switching the effector domain of FK506 to that in rapamycin, it is possible to change the targets from calcineurin to mTOR. The generation of a rapafucin library of macrocytes that contain FK506 and rapamycin binding domains should have great potential as new leads for developing drugs to be used for treating diseases.

With the completion of the sequencing and annotation of the human genome, a complete catalog of all human proteins encoded in the genome is now available. The functions of a majority of these proteins, however, remain unknown. One way to elucidate the functions of these proteins is to find small molecule ligands that specifically bind to the proteins of interest and perturb their biochemical and cellular functions. Thus, a major challenge for chemical biologists today is to discover new small molecule probes for new proteins to facilitate the elucidation of their functions. The recent advance in the development of protein chips has mitered an exciting new opportunity to simultaneously screen chemical libraries against nearly the entire human proteome. A single chip, in the form of a glass slide, is sufficient to display an entire proteome in duplicate arrays. Recently, a protein chip with 17,000 human proteins displayed on a single slide has been produced. A major advantage of using human protein chips for screening is that the entire displayed proteome can be interrogated at once in a small volume of assay buffer (<3 mL). Screening of human protein chips, however, is not yet feasible with most, if not all, existing chemical libraries due to the lack of a universal readout for detecting the binding of a ligand to a protein on these chips. While it is possible to add artificial tags to individual compounds in a synthetic library, often the added tags themselves interfere with the activity of ligands. Thus, there remains a need for new compounds and methods for screening chemical libraries against the human proteome.

SUMMARY OF THE INVENTION

One embodiment of the present invention is to provide a compound of the following structure:

R₁ and R₃ can independently be any of the following compounds:

R₂ and R₄ can independently be any of the following compounds:

Another embodiment of the present invention is to provide a compound of the following structure:

R₁, R_(2,) R₃ and R₄ are selected from the same groupings of compounds listed above.

Another embodiment of the present invention is to provide a compound that includes A15-34-2, A15-39-1, A15-39-2, A15-39-4, A15-39-6, A15-39-8, A15-39-15, A15-40-2, A15-40-4, A15-40-15, E15-32-2, E15-33-1, E15-33-2, E15-34-1, E15-34-2, E15-39-1, E15-39-2, E15-39-5, E15-40-2, E15-40-4, E15-S-19, E15-S-21, and E15-S-22.

Another embodiment of the present invention is to provide synthetic methods as outlined in the “Detailed Description of the Invention” for producing a Rapafucin library.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Number of compounds in library.

DETAILED DESCRIPTION OF THE INVENTION EXAMPLE 1

R₁ and R₃ in Scheme 1 are amino acids selected from the following group of amino acids:

R₂ and R₄ in Scheme 1 are amino acids selected from the following group of amino acids:

The synthesis of the amide mFKBD in Scheme 1 is as follows:

The synthesis of the ether mFKBD in Scheme 1 is as follows:

The general formula for a Rapafucin with an amide mFKBD is represented by “A”.

The general formula for a Rapafucin with an ether mFKBD is represented by “E”.

Specific Examples of “A” and “E” as well as their properties are listed in Table 1.

TABLE 1 Name Sequence Hillslope IC50(nM) Name Sequence Hillslope IC50(nM) A15-39-1 Gly-dmPhe- −0.9753 27.95 E15-40-2 Ala-dmPhe- −1.212 34.15 Pro-mVal Pro-mlle A15-39-2 Ala-dmPhe- −1.164 23.73 E15-40-4 Nva-dmPhe- −1.195 173.1 Pro-mVal Pro-mlle A15-39-4 Nva-dmPhe- −1.112 18 E15-32-2 Ala-dmPhe- −1.134 66.71 Pro-mVal Pro-mAla A15-39-6 Leu-dmPhe- −1.105 54.14 E15-33-1 Gly-dmPhe- −1.007 13.91 Pro-mVal Pro-mNIe A15-39-8 Phe-dmPhe- −1.191 54.99 E15-33-2 Ala-dmPhe- −1.017 9.76 Pro-mVal Pro-mNIe A15-39-15 Phg-dmPhe- −0.8952 16.51 E15-34-1 Gly-dmPhe- −1.494 28.54 Pro-mVal Pro-mLeu E15-39-1 Gly-dmPhe- −1.024 48.88 E15-34-2 Ala-dmPhe- −0.741 10.53 Pro-mVal Pro-mLeu E15-39-2 Ala-dmPhe- −1.125 33.54 A15-34-2 ** Ala-dmPhe- −0.3876 31.45 Pro-mVal Pro-mLeu E15-39-5 HoSMe- −0.8614 59.46 E15-S-19 Gly-dmPhe- −1.363 42.27 dmPhe-Pro- Pro-mNva mVal A15-40-2 Ala-dmPhe- −0.6276 34.4 E15-S-21 Gly-dmPhe- −1.314 154.9 Pro-mlle Pro-dmAla A15-40-4 Nva-dmPhe- −0.87 12.19 E15-S-22 Gly-dmPhe- −1.236 261.9 Pro-mlle Pro-Ach A15-40-15 Phg-dmPhe- −0.9138 100.1 Pro-mlle

Approximately, 45,000 compounds were obtained as part of the Rapafucin library (FIG. 1).

Although the invention has been described with reference to the above example, it will be understood that modifications and variations are encompassed within the spirit and scope of the invention. Accordingly, the invention is limited only by the following claims.

REFERENCES

The following reference is relied upon and incorporated herein in its entirety.

-   1. US 2014/0073581. 

What is claimed is:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein: R is

wherein R¹, R², R³, R⁴, and R⁵ are each independently selected from hydrogen, hydroxyl, alkoxy, cyano, alkylthio, amino, and alkylamino, and

wherein

is a resin; wherein one, two, three, or four of A¹, A², A³, A⁴, and A⁵ is N or P with the remaining being CH; wherein one, two, three, or four of B¹, B², B³ and B⁴ is O, N, or S with the remaining being CH or CH₂ as appropriate; wherein

is a single or double bond; X₁ is O or NR⁶; Y is —C(O)— or

X₂ is (CH₂)_(m), O, OC(O), NR⁶, NR⁶C(O); Z is

W is O, CH, CH₂, CR⁹, or C R¹⁰R¹¹; L₁ and L₂ are each independently a direct bond, substituted or unsubstituted —(C₁-C₆)alkyl-, substituted or unsubstituted —(CH₂)_(n)O(C₁-C₆)alkyl-, substituted or unsubstituted —(CH₂)_(n)C(O)(C₁-C₆)alkyl-, substituted or unsubstituted —(CH₂)_(n)C(O)O(C₁-C₆)alkyl-, substituted or unsubstituted —(CH₂)_(n)OC(O)(C₁-C₆)alkyl-, substituted or unsubstituted —(CH₂)_(n)NH(C₁-C₆)alkyl-, substituted or unsubstituted —(CH₂)_(n)C(O)NH(C₁-C₆)alkyl-, substituted or unsubstituted —(CH₂)_(n)S(C₁-C₆)alkyl-, substituted or unsubstituted —(CH₂)_(n)C(O)(CH₂)_(n)S(C₁-C₆)alkyl-, substituted or unsubstituted —(C₂-C₆)alkenyl-, substituted or unsubstituted —(CH₂)_(n)O(C₂-C₆)alkenyl-, substituted or unsubstituted —(CH₂)_(n)C(O)(C₂-C₆)alkenyl-, substituted or unsubstituted —(CH₂)_(n)C(O)O(C₂-C₆)alkenyl-, substituted or unsubstituted —(CH₂)_(n)OC(O)(C₂-C₆)alkenyl-, substituted or unsubstituted —(CH₂)_(n)NH(C₂-C₆)alkenyl-, substituted or unsubstituted —(CH₂)_(n)C(O)NH(C₂-C₆)alkenyl-, substituted or unsubstituted —(CH₂)_(n)S(C₂-C₆)alkenyl-, substituted or unsubstituted —(CH₂)_(n)C(O)(CH₂)_(n)S(C₂-C₆)alkenyl-, substituted or unsubstituted —(C₂-C₆)alkynyl-, substituted or unsubstituted —(CH₂)_(n)O(C₂-C₆)alkynyl-, substituted or unsubstituted —(CH₂)_(n)C(O)(C₂-C₆)alkynyl-, substituted or unsubstituted —(CH₂)_(n)C(O)O(C₂-C₆)alkynyl-, substituted or unsubstituted —(CH₂)_(n)OC(O)(C₂-C₆)alkynyl-, substituted or unsubstituted —(CH₂)_(n)NH(C₂-C₆)alkynyl-, substituted or unsubstituted —(CH₂)_(n)C(O)NH(C₂-C₆)alkynyl-, substituted or unsubstituted —(CH₂)_(n)S(C₂-C₆)alkynyl-, substituted or unsubstituted —(CH₂)_(n)C(O)(CH₂)_(n)S(C₂-C₆)alkynyl-, substituted or unsubstituted —(C₁-C₆)alkyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)O(C₁-C₆)alkyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)C(O)(C₁-C₆)alkyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)C(O)O(C₁-C₆)alkyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)OC(O)(C₁-C₆)alkyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)NH(C₁-C₆)alkyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)C(O)_(n)NH(C₁-C₆)alkyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)S(C₁-C₆)alkyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)C(O)(CH₂)_(n)S(C₁-C₆)alkyl-NR¹⁸—, substituted or unsubstituted —(C₂-C₆)alkenyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)O(C₂-C₆)alkenyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)C(O)(C₂-C₆)alkenyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)C(O)O(C₂-C₆)alkenyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)OC(O)(C₂-C₆)alkenyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)NH(C₂-C₆)alkenyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)C(O)_(n)NH(C₂-C₆)alkenyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)S(C₂-C₆)alkenyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)C(O)(CH₂)_(n)S(C₂-C₆)alkenyl-NR¹⁸—, substituted or unsubstituted —(C₂-C₆)alkynyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)O(C₂-C₆)alkynyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)C(O)(C₂-C₆)alkynyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)C(O)_(n)O(C₂-C₆)alkynyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)OC(O)(C₂-C₆)alkynyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)NH(C₂-C₆)alkynyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)C(O)NH(C₂-C₆)alkynyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)S(C₂-C₆)alkynyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)C(O)(CH₂)_(n)S(C₂-C₆)alkynyl-NR¹⁸—, substituted or unsubstituted —(C₁-C₆)alkyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)O(C₁-C₆)alkyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)C(O)(C₁-C₆)alkyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)C(O)O(C₁-C₆)alkyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)OC(O)(C₁-C₆)alkyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)NH(C₁-C₆)alkyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)C(O)NH(C₁-C₆)alkyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)S(C₁-C₆)alkyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)C(O)(CH₂)_(n)S(C₁-C₆)alkyl-C(O)—, substituted or unsubstituted —(C₂-C₆)alkenyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)O(C₂-C₆)alkenyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)C(O)(C₂-C₆)alkenyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)C(O)O(C₂-C₆)alkenyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)OC(O)(C₂-C₆)alkenyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)NH(C₂-C₆)alkenyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)C(O)NH(C₂-C₆)alkenyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)S(C₂-C₆)alkenyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)C(O)(CH₂)_(n)S(C₂-C₆)alkenyl-C(O)—, substituted or unsubstituted —(C₂-C₆)alkynyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)O(C₂-C₆)alkynyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)C(O)(C₂-C₆)alkynyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)C(O)O(C₂-C₆)alkynyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)OC(O)(C₂-C₆)alkynyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)NH(C₂-C₆)alkynyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)C(O)NH(C₂-C₆)alkynyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)S(C₂-C₆)alkynyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)C(O)(CH₂)_(n)S(C₂-C₆)alkynyl-C(O)—, —O—, —NH—, —S—, —S(O)—, —SO₂—, —Si—, and —B—, wherein each alkyl, alkenyl, and alkynyl group may be optionally substituted with alkyl, alkoxy, amino, hydroxyl, sulfhydryl, halogen, carboxyl, oxo, cyano, nitro, or trifluoromethyl; L₃ is a direct bond, substituted or unsubstituted —(C₁-C₆)alkyl-, substituted or unsubstituted —(CH₂)_(n)O(C₁-C₆)alkyl-, substituted or unsubstituted —(CH₂)_(n)C(O)(C₁-C₆)alkyl-, substituted or unsubstituted —(CH₂)_(n)C(O)_(n)O(C₁-C₆)alkyl-, substituted or unsubstituted —(CH₂)_(n)OC(O)(C₁-C₆)alkyl-, substituted or unsubstituted —(CH₂)_(n)NH(C₁-C₆)alkyl-, substituted or unsubstituted —(CH₂)_(n)C(O)NH(C₁-C₆)alkyl-, substituted or unsubstituted —(CH₂)S(C₁-C₆)alkyl-, substituted or unsubstituted —(CH₂)_(n)C(O)(CH₂)_(n)S(C₁-C₆)alkyl-, substituted or unsubstituted —(C₂-C₆)alkenyl-, substituted or unsubstituted —(CH₂)_(n)O(C₂-C₆)alkenyl-, substituted or unsubstituted —(CH₂)_(n)C(O)(C₂-C₆)alkenyl-, substituted or unsubstituted —(CH₂)_(n)C(O)O(C₂-C₆)alkenyl-, substituted or unsubstituted —(CH₂)_(n)OC(O)(C₂-C₆)alkenyl-, substituted or unsubstituted —(CH₂)_(n)NH(C₂-C₆)alkenyl-, substituted or unsubstituted —(CH₂)_(n)C(O)NH(C₂-C₆)alkenyl-, substituted or unsubstituted —(CH₂)_(n)S(C₂-C₆)alkenyl-, substituted or unsubstituted —(CH₂)_(n)C(O)(CH₂)_(n)S(C₂-C₆)alkenyl-, substituted or unsubstituted —(C₂-C₆)alkynyl-, substituted or unsubstituted —(CH₂)_(n)O(C₂-C₆)alkynyl-, substituted or unsubstituted —(CH₂)_(n)C(O)(C₂-C₆)alkynyl-, substituted or unsubstituted —(CH₂)_(n)C(O)O(C₂-C₆)alkynyl-, substituted or unsubstituted —(CH₂)_(n)OC(O)(C₂-C₆)alkynyl-, substituted or unsubstituted —(CH₂)_(n)NH(C₂-C₆)alkynyl-, substituted or unsubstituted —(CH₂)_(n)C(O)NH(C₂-C₆)alkynyl-, substituted or unsubstituted —(CH₂)_(n)S(C₂-C₆)alkynyl-, substituted or unsubstituted —(CH₂)_(n)C(O)(CH₂)_(n)S(C₂-C₆)alkynyl-, substituted or unsubstituted —(C₁-C₆)alkyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)O(C₁-C₆)alkyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)C(O)(C₁-C₆)alkyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)C(O)_(n)O(C₁-C₆)alkyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)OC(O)(C₁-C₆)alkyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)NH(C₁-C₆)alkyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)C(O)NH(C₁-C₆)alkyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)S(C₁-C₆)alkyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)C(O)(CH₂)_(n)S(C₁-C₆)alkyl-NR¹⁸—, substituted or unsubstituted —(C₂-C₆)alkenyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)O(C₂-C₆)alkenyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)C(O)(C₂-C₆)alkenyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)C(O)O(C₂-C₆)alkenyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)OC(O)(C₂-C₆)alkenyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)NH(C₂-C₆)alkenyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)C(O)NH(C₂-C₆)alkenyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)S(C₂-C₆)alkenyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)C(O)(CH₂)_(n)S(C₂-C₆)alkenyl-NR¹⁸—, substituted or unsubstituted —(C₂-C₆)alkynyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)O(C₂-C₆)alkynyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)C(O)(C₂-C₆)alkynyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)C(O)O(C₂-C₆)alkynyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)OC(O)(C₂-C₆)alkynyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)NH(C₂-C₆)alkynyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)C(O)NH(C₂-C₆)alkynyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)S(C₂-C₆)alkynyl-NR¹⁸—, substituted or unsubstituted —(CH₂)_(n)C(O)(CH₂)_(n)S(C₂-C₆)alkynyl-NR¹⁸—, substituted or unsubstituted —(C₁-C₆)alkyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)O(C₁-C₆)alkyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)C(O)(C₁-C₆)alkyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)C(O)O(C₁-C₆)alkyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)OC(O)(C₁-C₆)alkyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)NH(C₁-C₆)alkyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)C(O)NH(C₁-C₆)alkyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)S(C₁-C₆)alkyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)C(O)(CH₂)_(n)S(C₁-C₆)alkyl-C(O)—, substituted or unsubstituted —(C₂-C₆)alkenyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)O(C₂-C₆)alkenyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)C(O)(C₂-C₆)alkenyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)C(O)O(C₂-C₆)alkenyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)OC(O)(C₂-C₆)alkenyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)NH(C₂-C₆)alkenyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)C(O)NH(C₂-C₆)alkenyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)S(C₂-C₆)alkenyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)C(O)(CH₂)_(n)S(C₂-C₆)alkenyl-C(O)—, substituted or unsubstituted —(C₂-C₆)alkynyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)O(C₂-C₆)alkynyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)C(O)(C₂-C₆)alkynyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)C(O)O(C₂-C₆)alkynyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)OC(O)(C₂-C₆)alkynyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)NH(C₂-C₆)alkynyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)C(O)NH(C₂-C₆)alkynyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)S(C₂-C₆)alkynyl-C(O)—, substituted or unsubstituted —(CH₂)_(n)C(O)(CH₂)_(n)S(C₂-C₆)alkynyl-C(O)—, wherein each alkyl, alkenyl and alkynyl group may be optionally substituted with alkyl, alkoxy, amino, hydroxyl, sulfhydryl, halogen, carboxyl, oxo, cyano, nitro, or trifluoromethyl; each m is independently an integer selected from 0, 1, 2, 3, 4, 5, and 6; each n is independently an integer selected from 0, 1, 2, 3, 4, 5, and 6; R⁶ is hyrdrogen or alkyl; R⁷ and R⁸ are each independently selected from hydrogen, hydroxy, alkyl, alkoxy, cyano, alkylthio, amino, and alkylamino, and OPG, wherein OPG is a protecting group; R⁹, R¹⁰, R¹¹ and are each independently selected from hydrogen, hydroxy, alkyl, alkoxy, cyano, alkylthio, amino, and alkylamino, and OPG, wherein OPG is a protecting group; wherein the Effector Domain has Formula II:

wherein: R₁₂, R¹⁴, R¹⁶, and R¹⁸ are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted perfluoroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl amino, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkylaryl, (CH₂)_(n)CN, (CH₂)_(n)CF₃, (CH₂)_(n)C₂F₅. R¹³, R¹⁵, and R¹⁷ are each independently the sidechains of naturally occurring amino acids and their modified forms including but are not limited to D-amino acid configuration, or hydrogen, halogen, amino, cyano, nitro, trifluoromethyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted perfluoroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl amino, substituted or unsubstituted alkylthio, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkylaryl, substituted or unsubstituted (CH₂)_(n)-aryl, substituted or unsubstituted (CH₂)_(n)-heteroaryl, (CH₂)_(n)CN, (CH₂)_(n)CF₃, (CH₂)_(n)C₂F₅, (CH₂)_(n)OR¹⁹, (CH₂)_(n)C(O)R¹⁹, (CH₂)_(n)C(O)OR¹⁹, (CH₂)_(n)OC(O)R¹⁹, (CH₂)_(n)NR²⁰R²¹, (CH₂)_(n)C(O)NR²⁰R²¹, (CH₂)_(n)NR²²C(O)R¹⁹, (CH₂)_(n)NR²²C(O)OR₁₉, (CH₂) NR²²C(O)NR²⁰R²¹, (CH₂)_(n)SR¹⁹, (CH₂)_(n)S(O)_(j)NR²⁰R²¹, (CH₂)_(n)NR²²(O)_(j)R¹⁹, or —(CH₂)_(n)NR²²S(O)_(j)NR²⁰R²¹; R¹² and R¹³, R¹⁴ and R¹⁵, R¹⁶ and R¹⁷ can be convalently connected to form a substituted or unsubstituted 5-, 6-, or 7-membered heterocycle. each k is independently an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each j is independently an integer selected from 0, 1, and 2; R¹⁹, R²⁰, R²¹, and R²² are each independently hydrogen, halogen, amino, cyano, nitro, trifluoromethyl, alkyl, alkenyl, alkynyl, cycloalkyl, perfluoroalkyl, alkoxy, alkylamino, alkylthio, aryl, alkylaryl, heteroalkyl, heterocycloalkyl, heteroaryl, or heteroalkylaryl, or R¹⁹ and R²² are as described above, and R²⁰ and R²¹, together with the N atom to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered heterocycloalkyl or a substituted or unsubstituted 5-membered heteroaryl, wherein each of the above groups listed for R¹³, R¹⁵, and R¹⁷ may be optionally independently substituted with 1 to 3 groups selected from halogen, amino, cyano, nitro, trifluoromethyl, alkyl, alkenyl, alkynyl, cycloalkyl, perfluoroalkyl, alkoxy, alkylamino, alkylthio, aryl, alkylaryl, heteroalkyl, heterocycloalkyl, heteroaryl, heteroalkylaryl, (CH₂)_(n)CN, (CH₂)_(n)CF₃, (CH₂)_(n)C₂F₅, (CH₂)_(n)O₁₉, (CH₂)_(n)C(O)R¹⁹, (CH₂)_(n)C(O)OR¹⁹, (CH₂)_(n)OC(O)R¹⁹, (CH₂)_(n)NR²⁰R²¹, (CH₂)_(n)C(O)NR²⁰R²¹, (CH₂)_(n)NR²²C(O)R¹⁹, (CH₂)_(n)NR²²C(O)OR₁₉, (CH₂)_(n)NR²²C(O)NR²⁰R²¹, (CH₂)_(n)SR¹⁹, (CH₂)_(n)S(O)_(j)NR²⁰R²¹, (CH₂)_(n)NR²²S(O)_(j)R¹⁹, or —(CH₂)_(n)NR²²S(O)_(j)NR²⁰R²¹; or wherein the Effector Domain has Formula III:

wherein: each k is independently an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; R²³ is a hydrogen or alkyl; X₃ is substituted or unsubstituted —(C₁-C₃₀)alkyl-, alkenyl-, alkynyl- with each carbon individually assuming one of the following redox states: CH₂, CH—OH, C(O); or wherein the Effector Domain has Formula IV:

wherein: X₄ is substituted or unsubstituted —(C₁-C₃₀)alkyl-, alkenyl-, alkynyl- with each carbon individually assuming one of the following redox states: CH₂, CH—OH, C(O). Or wherein the Effector Domain has Formula V:

wherein: R²⁴ and R²⁵ are each a hydrogen or alkyl; X₅ is substituted or unsubstituted —(C₁-C₃₀)alkyl-, alkenyl-, alkynyl- with each carbon individually assuming one of the following redox states: CH₂, CH—OH, C(O). Or wherein the Effector Domain has Formula VI:

wherein: X₆ is substituted or unsubstituted —(C₁-C₃₀)alkyl-, alkenyl-, alkynyl- with each carbon individually assuming one of the following redox states: CH₂, CH—OH, C(O).
 2. The compound of formula I of claim 1, wherein L₃ is as defined in claim 1 but not

with R²⁶ being hydrogen or alkyl.
 3. The compound of formula I of claim 1, wherein R is as defined in claim 1 but not

wherein R³ is hydrogen, hydroxyl, or OPG, wherein PG is a protecting group, or

wherein

is a resin; wherein R² is hydrogen, hydroxyl, or alkoxy; and wherein R¹, R⁴, and R⁵ are each independently hydrogen or no substituent as dictated by chemical bonding; wherein

is a single or double bond.
 4. The compound of formula I of claim 1, wherein L₁ and L₂ and the Effector Domain are as defined in claim 1 but L₁ and L₂ not each independently direct bond, substituted or unsubstituted —(C₁-C₆)alkyl-, substituted or unsubstituted —(CH₂)_(n)O(C₁-C₆)alkyl-, substituted or unsubstituted —(CH₂)_(n)C(O)—, substituted or unsubstituted —(CH₂)_(n)C(O)(C₁-C₆)alkyl-, substituted or unsubstituted —(CH₂)_(n)C(O)O(C₁-C₆)alkyl-, substituted or unsubstituted —(CH₂)_(n)NH(C₁-C₆)alkyl-, substituted or unsubstituted —(CH₂)_(n)C(O)NH(C₁-C₆)alkyl-, substituted or unsubstituted —(CH₂)_(n)S(C₁-C₆)alkyl-, substituted or unsubstituted —(CH₂)_(n)C(O)(CH₂)_(n)S(C₁-C₆)alkyl-, substituted or unsubstituted —(C₂-C₆)alkenyl-, substituted or unsubstituted —(CH₂)_(n)O(C₂-C₆)alkenyl-, substituted or unsubstituted —(CH₂)_(n)C(O)(C₂-C₆)alkenyl-, substituted or unsubstituted —(CH₂)_(n)C(O)O(C₂-C₆)alkenyl-, substituted or unsubstituted —(CH₂)_(n)NH(C₁-C₆)alkenyl-, substituted or unsubstituted —(CH₂)_(n)C(O)NH(C₂-C₆)alkenyl-, substituted or unsubstituted —(CH₂)_(n)S(C₂-C₆)alkenyl-, substituted or unsubstituted —(CH₂)_(n)C(O)(CH₂)_(n)S(C₂-C₆)alkenyl-, substituted or unsubstituted —(C₂-C₆)alkynyl-, substituted or unsubstituted —(CH₂)_(n)O(C₂-C₆)alkynyl-, substituted or unsubstituted —(CH₂)_(n)C(O)(C₂-C₆)alkynyl-, substituted or unsubstituted —(CH₂)_(n)C(O)O(C₂-C₆)alkynyl-, substituted or unsubstituted —(CH₂)_(n)NH(C₁-C₆)alkynyl-, substituted or unsubstituted —(CH₂)_(n)C(O)NH(C₂-C₆)alkynyl-, substituted or unsubstituted —(CH₂)_(n)S(C₂-C₆)alkynyl-, substituted or unsubstituted —(CH₂)_(n)C(O)(CH₂)_(n)S(C₂-C₆)alkynyl-, wherein each alkyl, alkenyl, and alkynyl group may be optionally substituted with alkyl, alkoxy, amino, carboxyl, cyano, nitro, or trifluoromethyl; and the Effector Domain is a compound of Formula VIII

wherein R₁₂, R₁₄, R_(14′), R₁₆, and R²⁷ are not each independently hydrogen or alkyl and R¹³, R¹⁴, R^(14′), and R¹⁶ are not each independently hydrogen, halogen, amino, cyano, nitro, trifluoromethyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted perfluoroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkylaryl, (CH₂)_(n)CN, (CH₂)_(n)CF₃, (CH₂)_(n)C₂F₅, (CH₂)_(n)OR¹⁹, (CH₂)_(n)C(O)R¹⁹, (CH₂)_(n)C(O)OR¹⁹, (CH₂)_(n)OC(O)R¹⁹, (CH₂)_(n)NR²⁰R²¹, (CH₂)_(n)C(O)NR²⁰R²¹, (CH₂)_(n)NR²²C(O)R¹⁹, (CH₂)_(n)NR²²C(O)OR¹⁹, (CH₂)_(n)NR₂₂C(O)NR₂₀R₂₁, (CH₂)_(n)S(O)_(j)NR²⁰R²¹, (CH₂)_(n)NR₂₂S(O)_(j)R¹⁹, or —(CH₂)_(n)NR²²S(O)_(j)NR²⁰R²¹; n is an integer selected from 0, 1, 2, 3, 4, 5, and 6; j is an integer selected from 0, 1, and 2; R¹⁹, R²⁰R²¹, and R²² are each independently hydrogen, halogen, amino, cyano, nitro, trifluoromethyl, alkyl, alkenyl, alkynyl, cycloalkyl, perfluoroalkyl, alkoxy, alkylamino, alkylthio, aryl, alkylaryl, heteroalkyl, heterocycloalkyl, heteroaryl, or heteroalkylaryl, or R¹⁹ and R²² are as described above, and R²⁰ and R²¹, together with the N atom to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered heterocycloalkyl or a substituted or unsubstituted 5-membered heteroaryl, wherein each of the above groups listed for R¹³, R¹⁵, and R¹⁷ may be optionally independently substituted with 1 to 3 groups selected from halogen, amino, cyano, nitro, trifluoromethyl, alkyl, alkenyl, alkynyl, cycloalkyl, perfluoroalkyl, alkoxy, alkylamino, alkylthio, aryl, alkylaryl, heteroalkyl, heterocycloalkyl, heteroaryl, heteroalkylaryl, (CH₂)_(n)CN, (CH₂)_(n)CF₃, (CH₂)_(n)C₂F₅, (CH₂)_(n)OR¹⁹, (CH₂)_(n)C(O)R¹⁹, (CH₂)_(n)C(O)OR¹⁹, (CH₂)_(n)OC(O)R¹⁹, (CH₂)_(n)NR²⁰R²¹, (CH₂)_(n)C(O)NR²⁰R²¹, (CH₂)_(n)NR₂₂C(O)R₁₉, (CH₂)_(n)NR²²C(O)OR¹⁹, (CH₂)_(n)NR²²C(O)NR²⁰R²¹, (CH₂)_(n)SR¹⁹, (CH₂)_(n)S(O)_(j)NR²⁰R²¹, (CH₂)_(n)NR²²S(O)_(j)R¹⁹, or —(CH₂)_(n)NR²²S(O)_(j)NR²⁰R²¹.
 5. The compound of formula I of claim 1, wherein L₃ is —CH₂CH₂—; R iS

R¹, R⁴, R⁵ and R⁶ are each hydrogen; R² and R³ are each methoxy; m=0; Y is

X₂ is O or NR⁶C(O) L₁ is —CH₂—C(O)—or —(CH₂)₂C(O)—; Z is

L₂ is —OCO—CH═CH—(CH₂)₂N(Me)—;
 6. The compound of claim 5, wherein the effector domain of formula II has formula VII

Wherein R¹², R¹⁴, R^(14′), and R¹⁶ are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted perfluoroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkylaryl, (CH₂)_(n)CN, (CH₂)_(n)CF₃, (CH₂)_(n)C₂F₅. R¹³, R¹⁵, R^(15′) and R¹⁷ are each independently the sidechains of naturally occurring amino acids and their modified forms including but are not limited to D-amino acid configuration, or hydrogen, halogen, amino, cyano, nitro, trifluoromethyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted perfluoroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkylaryl, substituted or unsubstituted (CH₂)_(n)-aryl, substituted or unsubstituted (CH₂)_(n)-heteroaryl, (CH₂)_(n)CN, (CH₂)_(n)CF₃, (CH₂)_(n)C₂F₅, (CH₂)_(n)OR¹⁹, (CH₂)_(n)C(O)R₁₉, (CH₂)_(n)C(O)OR¹⁹, (CH₂)_(n)OC(O)R¹⁹, (CH₂)_(n)NR²⁰R²¹, (CH₂)_(n)C(O)NR²⁰R²¹, (CH₂)_(n)NR²²C(O)R¹⁹, (CH₂)_(n)NR²²C(O)OR¹⁹, (CH₂)_(n)NR²²C(O)NR²⁰R²¹, (CH₂)_(n)SR¹⁹, (CH₂)_(n)S(O)_(j)NR²⁰R²¹, (CH₂)_(n)NR²²S(O)_(j)R¹⁹, or —(CH₂)_(n)NR²²S(O)_(j)NR²⁰R²¹. R¹² and R¹³, R¹⁴ and R¹⁵, R^(14′) and R^(15′), R¹⁶ and R¹⁷ can be covalently connected to form a substituted or unsubstittued 5-, 6-, or 7-membered heterocycle.
 7. The compound of claim 5, wherein the effector domain of formula II has formula VIII -AA₁-AA₂-AA₃-AA₄-  (VIII) wherein AA₁, AA₂, AA₃ and AA₄ are each independently selected from:


8. The compound of claim 5, wherein X₂ is O and L₁ is CH₂—C(O)—.
 9. The compound of claim 5, wherein X₂ is NR⁶C(O) and L₁ is —(CH₂)₂C(O)—.
 10. A method for synthesizing a compound or libraries of compounds selected from those described in claim 1 comprising the steps disclosed in the “Detailed Description of the Invention”.
 11. A method of using a hybrid cyclic library based on the immunophilin ligand family of natural products FK506 and rapamycin, to screen for compounds for treating cancer.
 12. A method of using a hybrid cyclic library based on the immunophilin ligand family of natural products FK506 and rapamycin, to screen for compounds for treating autoimmune disease. 